Static magnetic fields in regenerative medicine

All organisms on Earth live in the weak but ubiquitous geomagnetic field. Human beings are also exposed to magnetic fields generated by multiple sources, ranging from permanent magnets to magnetic resonance imaging (MRI) in hospitals. It has been shown that different magnetic fields can generate various effects on different tissues and cells. Among them, stem cells appear to be one of the most sensitive cell types to magnetic fields, which are the fundamental units of regenerative therapies. In this review, we focus on the bioeffects of static magnetic fields (SMFs), which are related to regenerative medicine. Most reports in the literature focus on the influence of SMF on bone regeneration, wound healing, and stem cell production. Multiple aspects of the cellular events, including gene expression, cell signaling pathways, reactive oxygen species, inflammation, and cytoskeleton, have been shown to be affected by SMFs. Although no consensus yet, current evidence indicates that moderate and high SMFs could serve as a promising physical tool to promote bone regeneration, wound healing, neural differentiation, and dental regeneration. All in vivo studies of SMFs on bone regeneration and wound healing have shown beneficial effects, which unravel the great potential of SMFs in these aspects. More mechanistic studies, magnetic field parameter optimization, and clinical investigations on human bodies will be imperative for the successful clinical applications of SMFs in regenerative medicine.


I. INTRODUCTION
Regenerative medicine is an emerging multidisciplinary science that aims to develop methods to regrow, repair, or replace damaged/ diseased cells, organs, or tissues 1 with the goal of restoring our physiology to its original condition and showing promising results across multiple systems.A growing body of data indicates that magnetic field has the potential to be used in regenerative medicine.Depending on whether magnetic fields change over time, they can be divided into time-varying magnetic fields and static magnetic fields (SMFs).The focus of this article is SMFs, whose intensity and direction are constant.As the fundamental units of regenerative medicine, stem cells are undifferentiated cells with clonal potential, capable of self-renewal and differentiation, 3 and are mainly responsible for the regeneration and development of organs and tissues. 2,4It is interesting that stem cell is one of the most sensitive cell types to SMFs.6][7] In addition, SMFs have been shown to promote tissue repair, expedite wound healing, and to maintain bone health. 8The purpose of this review is to summarize the research progress of SMFs on regenerative medicine related aspects, including animal and cellular studies about bone regeneration, wound healing, nerve, dental pulp, and muscle.It is obvious that both positive and negative results are present in the literature, and we try to summarize and analyze them to find some consensus, including SMF parameters and biological systems with beneficial effects, which could provide a foundation for clinical exploration, as well as future systematic and mechanistic studies.

II. BONE REGENERATION
Bone regeneration has always been a hot topic in magnetic fields and regenerative medicine.Studies have shown the positive effects of pulsed electromagnetic fields (PEMFs) in bone regeneration, which generate weak electrical currents in bone through external coils on the cast or skin.Food and Drug Administration (FDA) has approved it as an aid in osteoporosis and osteoarthritis treatment.0][11] For SMFs, although they have not been FDA-approved, there are also quite a few reports related to its potential application in bone regeneration (Table I), which show that SMFs have multiple beneficial effects on the bone systems both in vitro and in vivo.

A. Bone regeneration in vitro
Osteoblasts and osteoclasts are cells that work together to form new bones and break down old/damaged bones.Several in vitro experiments on osteoblasts (build new bones) and osteoclasts (dissolve old/damaged bones) have shown that SMF affects them in a magnetic field intensity and cell-type dependent manner.For example, in 2014, Shang's team found that both 500 nT hypomagnetic field and 200 mT moderate SMF decreased osteoblast differentiation, while 16 T high SMF increased osteoblast differentiation. 12Moreover, it is interesting that they observed opposite effects of these SMFs on osteoclasts: the 500 nT and 200 mT SMF increased osteoclast differentiation, but the 16 T SMF decreased osteoclast differentiation. 13These demonstrate that the effect of SMFs on bone regeneration is related to both magnetic field strength and cell type and indicate the bone promotion effects of high SMFs.Moreover, Yamamoto et al. treated cultured rat cranial osteoblasts with 160 mT SMF for 20 days and found increased values of the total area, number, and mean size of bone nodules. 14urthermore, Zhang et al. found that after placing Raw264.7 cells in 1-2 T SMFs for 4 days, the osteoclast formation in the presence of Ferumoxytol was reduced. 15Kotani et al. also found that 8 T high SMF can align both mouse osteoblastic MC3T3-E1 cells and the orientation of bone formation. 16,17ther than osteoblasts and osteoclasts, there are also studies investigating the effects of SMFs on bone regeneration by acting on bone marrow and umbilical cord-derived mesenchymal stem cells (MSCs).For example, in 2015, Kim et al. exposed human BMSCs to 3, 15, or 50 mT SMFs and found that these moderate intensity SMFs promoted the proliferation and osteogenic differentiation of human BMSCs, especially at 15 mT. 18In 2019, He et al. examined the osteogenic effect of 50, 100, and 150 mT SMFs on human BMSCs in three-dimensional-printed (3DP) scaffolds and found that the SMFs promoted osteogenic differentiation of hBMSCs. 19Moreover, there are multiple studies reported that 200-400 mT SMFs can prevent BMSC lipogenic differentiation, increase osteogenic differentiation, 20 stimulate chondrogenic differentiation, 21 enhance mandibular BMSCs chondrogenesis and proliferation, 22 accelerate mandibular condylar chondrocytes (MCCs) osteogenesis, 23 and promote the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). 24SMFs can also significantly attenuate dexamethasone or all-trans retinoic acid-induced bone loss in mice. 20ost in vitro studies in the literature showed beneficial effects of SMFs on bone regeneration, with only a few exemptions.For example, Shang's team found that both 500 nT hypomagnetic field and 200 mT moderate SMF decreased osteoblast differentiation 12 and increased osteoclast differentiation; 13 Hsieh et al. found that 3 T SMF inhibited the growth of human chondrocytes in vitro and affected the recovery of damaged knee cartilage in pig models. 25However, it is interesting that as far as we know, all animal studies in the literature demonstrated beneficial effects on bone regeneration, which will be introduced below.

B. Bone regeneration in vivo
Several rodent studies have been conducted to determine the effectiveness of SMFs on bone growth, which indicate that SMFs promote not only bone healing process but also bone formation in vivo. 8For example, He et al. used 100 mT SMF to treat a rat model of bone defect for 6 and 12 weeks and found that SMF promoted bone regeneration and osseointegration. 19Tapered rod-shape magnets of 180 mT were implanted transcortically into the middle diaphysis of rat femurs for 12 weeks, which prevented the loss of bone mineral density (BMD) caused by the implantation operation. 26Sun et al. treated osteoarthritis (OA) mice with 200 mT SMF for 2 weeks, which stimulated chondrogenesis, enhanced the cellular matrix of cartilage, and attenuated the pathological progression of cartilage destruction in OA mice. 27In 2021, the Shang's group found that 4 weeks of SMFs treatment at 200-400 mT facilitated the recovery of unloading-induced bone loss by inhibiting bone resorption in reloaded mice. 28In the same year, they also reported that mice exposed to 2-4 T SMFs for 28 days have improved bone microstructure and mechanical properties. 29here are also a few studies reported positive effects of SMFs on diabetic bone formation and postmenopausal-induced osteoporosis.For example, Zhang et al. found that 16 weeks of 4 mT SMF treatment can stimulate the bone formation in streptozotocin (STZ)-treated diabetic rats, prevent bone architectural deterioration and strength reduction. 30Taniguchi et al. found that 30-200 mT SMFs treatment for 12 weeks can increase the bone density and bone area of ovariectomized (OVX) rats. 31Xu et al. implanted a 180 mT small disk magnet on the right side of the lumbar spine of OVX rats and found that the bone density of the lumbar vertebrae near the magnet was significantly increased after 6 weeks. 32 Effects of SMFs combined with magnetic nanoparticles on bone regeneration Some investigations have also been conducted to explore how the combination of SMFs with other therapies affects bone regeneration, and the focus here is on the combination of SMFs with magnetic nanoparticles (MNPs) (Table II).Combining 15 mT SMF and MNPs-added polycaprolactone (PCL) nanocomposite scaffolds was found to promote osteoblast differentiation and bone formation both in vitro and in vivo.35 Filippi et al. also observed that 50 mT SMF treatment for 21 days stimulated the osteogenic and angiogenic potential of constructs composed of MNPs doped into polyethylene glycol (PEG)based hydrogels containing human adipose tissue stromal vascular fraction (SVF) cells.36 In addition, Boda et al. found that 100 mT SMF induced proliferation arrest of human mesenchymal stem cells (MSCs) cultured on the magnetic composite hydroxyapatite (HA)-magnetite (Fe 3 O 4 ), leading to early cell differentiation and osteogenic formation.37 Also, Wu et al. cultured BMSCs with 100 mT SMF and Fe 3 O 4 nanoparticles for 24 h and found that low doses of Fe 3 O 4 nanoparticles combined with SMF could enhance osteogenesis and angiogenesis.38 While most studies showed positive effects, Yamaguchi-Sekino et al. reported that exposure to 7 T SMF for 3 h/day for 6 days had no effect on the expression of genes and proteins of osteogenic markers of MSCs in tricalcium phosphate (TCP)/MSC constructs.39

III. WOUND HEALING
There are also multiple studies indicating the promoting effects of SMFs on wound healing (Table III).Since impaired wound healing is very common in diabetic patients, quite a few studies have performed their wound healing experiments in diabetic rodent models.For  42 The ability of SMFs to promote wound healing has also been demonstrated in some other experiments in non-diabetic animal models.For example, the 2.3 mT magnets were placed on standardized wounds on the backs of rats, which accelerated the rate of wound healing. 43It is interesting that a case study involving a 51-year-old paraplegic woman with an abdominal wound that had been present for one year showed that the wound was completely healed after one month of applying a magnet to a conventional wound dressing, 44 although no further detail about the magnet parameters was provided.
There are also experiments investigated the combined effects of SMFs with MNPs on wound healing.For example, BMSCs cocultured with 100 mT SMF and MNPs Fe 3 O 4 can enhance the wound healing of rats with dorsal wounds by improving angiogenesis and fibroblast function. 45Wang et al. found that 80 mT SMF combined with magneto-deformable cobalt ferrite nanoparticles/polyvinyl alcohol matrix can also accelerate rats wound healing. 46

IV. NERVE CELLS
The nervous system, including the brain, spinal cord, and neurons, is an important target of magnetic fields.It has been shown that SMF exposure has a strong modulatory impact on neural tissues (Table IV).For example, Ben Yakir-Blumkin et al. found that continuous exposure of young adult rats to low-intensity SMFs of <10 mT for 3 weeks significantly enhanced the generation of new doublecortinexpressing cells in the sub-ventricular zone (SVZ) and neocortex. 49xposure of rat olfactory ensheathing cells (OECs) to 30, 50, and 70 mT SMFs led to filamentous pseudopod formation, cell morphology changes and cell migration promotion. 50Nakamichi et al. discovered that 100 mT SMF considerably reduced cell proliferation of neural progenitor cells (NPCs) and promoted their differentiation into neurons. 51Pacini et al. treated normal human neuronal cells (FNC-B4) with SMF generated by 200 mT magnetic resonance tomography for 120 min, and found that SMF caused significant FNC-B4 morphology changes and promoted neural differentiation. 52Prasad et al. stimulated human oligodendrocyte precursor cells (OPCs) with 300 mT SMF for 2 weeks (2 h/day) and observed enhanced myelin formation in oligodendrocytes, increased cell differentiation and myelination potential. 53Ho et al. discovered that 500 mT SMF increased the production of neurospheres and the proliferative activity of mouse NPCs. 54Eguchi et al. found that 8 T SMF treatment for 60 h induced parallel orientation of the Schwann cells along the SMF direction.In contrast, due to the strong diamagnetic anisotropy of collagen, the Schwann cells were oriented perpendicularly to SMF when they were mixed with collagen, 55 which indicates that the orientation of cells are strongly affected by their surrounding materials.
Besides using SMFs alone, several studies have combined SMFs with other treatments for neural differentiation and regeneration.For example, Birk et al. found that 80 mT SMF stimulated insulin-like growth factor 1 (IGF1)-induced human satellite cell proliferation during the first days of myogenesis. 56They also investigated the effects of combining pro-myogenic differentiation hepatocyte growth factor (HGF) at 80 mT SMF on human satellite cell cultures and reported

V. MYOBLASTS
There are also some studies reported the effects of SMF on myoblasts, and most of them showed positive effects.For example, Surma et al. treated satellite cells with 60-400 lT of weak SMFs and found that the weak SMFs accelerated the development of skeletal muscle cells and led to multinucleated hypertrophic myotube formation. 59ekhite et al. found that 1 mT SMF enhanced cardiomyogenesis in Flk-1þ cardiac progenitor cells. 60Stern-Straeter et al. observed an increase in myotube formation in human satellite cells in $80 mT SMF-treated growth medium (GM). 62Similarly, Coletti et al. found that 80 mT SMF treatment for 5 days accelerated myogenic differentiation of rat L6 myogenic cells and counteracted the inhibition effects of tumor necrosis factor (TNF) on myogenesis. 63However, there are also a few negative results.For example, Li et al. found that the proliferation, migration, and adhesion potential of human umbilical artery smooth muscle cells (hUASMCs) were significantly decreased after exposure to 5 mT SMF for 48 h. 61Kim et al. found that 200 mT SMF decreased the growth of cultured myoblast C2C12 cells. 64

VI. DENTAL PULP STEM CELLS
There are a few studies about the potential application of SMFs in dental regeneration, especially the effects of SMFs on DPSCs.For example, Na et al. found that 1 mT SMF promoted DPSC proliferation, migration, adult dentin differentiation, and mineralization. 65Zheng et al. reported that 1, 2, and 4 mT SMFs rearranged the actin filaments of DPSCs, effectively induced DPSCs odontogenesis, stimulated the migration, and proliferation of DPSCs. 7For stronger magnets, Lew  66 Moreover, they found that 400 mT treatment for 20 days promoted migration and reparative dentin formation. 67In addition to DPSCs, Hsu and Chang found that although 290 mT SMF treatment of dental pulp cells (DPCs) for 9 days did not affect their proliferation, the osteogenic differentiation and mineralization were accelerated. 68

VII. OTHER STEM CELLS
In addition to bone regeneration, neural differentiation, and wound healing, stem cells research related to SMFs also includes effects on other stem cells (Table V), among which are MSCs.MSCs have the ability to differentiate to multiple cell types and can differentiate into a variety of tissues, such as nerve, heart, bone, and tendon.This ability of multidirectional differentiation provides an important potential for the treatment of many human diseases.For example, Jouni et al. found that after culturing rat BMSCs in 4 mT SMF for 96 h, SMF exaggerated the differentiation potential of BMSCs to primordial germ cells (PGCs). 69They treated rat BMSCs with 4, 7, and 15 mT SMFs, and found that the cell survival and proliferation were negatively correlated with SMF intensity and duration. 70Sarvestani et al. reported that 15 mT SMF did not have any detectable impact on the cell cycle of rat BMSCs. 71Sadri et al. revealed that 18 mT or 24 mT SMFs affected the cell cycle progression, proliferation rate and arrangement of human MSCs, and induced cell differentiation. 72Wu et al. found that $140 mT of SMFs exposure promoted the proliferation of MSCs. 73aredziak et al. found that 500 mT SMF treatment for 7 days enhanced the viability and proliferation rate of human ASCs. 6Wang et al. discovered that after exposing ASCs to 500 mT SMF for 7 days, the cell viability and proliferation were mildly reduced. 74They also treated adipose-derived mesenchymal stem cells (AdMSCs) of canine and equine with 500 mT SMF and showed that canine AdMSCs significantly reduced proliferation rate, whereas the proliferation activity of equine AdMSCs was enhanced. 75Sch€ afer et al. found that viability, proliferation rate, and the chondrogenic differentiation capacity of superparamagnetic particles of iron oxide (SPIO)-labeled or unlabeled human MSCs were not affected by 600 mT SMF. 76Dikina et al. found that both static and time-varying magnetic fields generated by 1.44-1.45T permanent magnets had no effect on cartilage development in human MSCs. 77ome groups have also tested SMFs on other stem cells.For example, Van Huizen et al. found that weak SMFs altered Schmidtea mediterranea (CIW4) stem cell proliferation and subsequent differentiation, and these effects were related to magnetic field strength. 78ullivan et al. applied 35-120 mT SMFs to both fetal lung (WI-38) and adult skin fibroblasts and found that SMFs significantly reduced their initial attachment and subsequent growth. 79Song et al. found that the upward direction $100-200 mT SMFs for 3 weeks could inhibit DNA synthesis and regeneration in hepatocytes, which caused detrimental effects on the lifespan of heavy drinking mice. 80Iachininoto et al. found that 1.5 or 3 T gradient magnetic fields (GMFs) emitted by magnetic resonance imaging (MRI) exposure of the blood donor CD34þ cells in vitro for 72 h did not affect the cell proliferation or clonogenic potential. 81Schwenzer et al. found that electrostatic fields alone and the turbo spin-echo sequence of 3 T SMF had no effect on clonogenic capacity, proliferation, or cell cycle of eugenic human lung fibroblasts. 82Monzen et al. found that 16 h of 10 T SMF treatment enhanced differentiation of CD34þ cells that were isolated from human placental and umbilical cord blood to megakaryocyte/erythroid progenitors (MEP) and/or promote proliferation of bipotent MEP. 83

VIII. ANALYSIS OF THE DIFFERENTIAL EFFECTS AND MECHANISMS
From the information above, it is clear that SMFs can affect multiple systems in our bodies that are related to regenerative medicine.However, the results are not always consistent, which may be attributed to multiple aspects, such as magnetic field parameters, cell and tissue types, and treatment procedure. 4For instance, Shang's team treated osteoblasts MC3T3-E1 cells and osteoclasts Raw264.7 cells with SMFs of 500 nT, 0.2 T, and 16 T and not only found that lower vs higher intensity SMFs generated opposite effects, and osteoblasts and osteoclasts also responded total differently to SMFs. 12,13Feng et al. found it interesting that while both vertically upward and downward SMFs can promote wound healing, the vertically downward SMF is more effective. 48Song et al. also found that the downward SMF had a promotion effects on the liver regeneration after high dose of alcohol consumption, but not the upward SMFs, which is due to the opposite direction Lorentz forces exerted on the negatively charged DNA during DNA synthesis. 80n addition to magnetic field parameters themselves, there are also multiple other factors that have led to the differential results in the literature.For example, Sullivan et al. showed that reactive oxygen species (ROS) levels increased 37% in WI-38 cells exposed to SMFs during the first 18 h after seeding, but no elevation in oxidant levels was observed after a prolonged 5-day exposure.They found that SMF exposure decreased cell attachment by <10% in relatively young cultures, but by >60% in later passage cultures. 79Similarly, for the same type of cells (BMSCs) and the same SMF intensity (15 mT), Javani et al. observed decreased cell survival and proliferation, 70  .Moreover, Ogiue-Ikeda et al. revealed that the spindle shaped smooth muscle A7r5 cells were not oriented after 60 h of exposure to SMF in low-density culture, whereas those that were oriented by the magnetic field only when the cells were actively proliferating at high cell density, 85 while the mechanism is unknown.To make things even more complicated, Birk et al. showed that the same SMF in combination with different factors can result in completely different results. 56,57hey found that during the first days of myogenesis, the 80 mT SMF stimulated IGF1-induced human satellite cell proliferation and enhanced gene expression of myogenic maturation markers. 56owever, when they replaced the IGF1 with HGF, they did not observe any significant changes. 57hile the bioeffects of SMFs still lack consensus, in general, people are trying to investigate the molecular changes after SMF treatment, aiming to understand the underlying mechanism, but has no conclusion yet.In general, multiple cellular events and signaling pathways were found to be changed after SMF exposure.For example, people think that SMFs may accelerate regeneration of bone, nerve, muscle, etc., by influencing expression of markers related to their regeneration, such as Mash1, Math1, alkaline phosphatase (ALP), osteocalcin (OCN), and myogenic factor-5 (MYF5). 14,18,34,51,56,86In addition, pathways, such as transforming growth factor-b (TGF-b), bone morphogenic protein (BMP)-Smad, and AKT, are also affected. 7,21,23,24,33,87]69,73 It is also interesting that receptor activator of NF-jB (RANK), matrix metalloproteinase 9 (MMP9) and V-ATPase, which are related to osteoclasts activation and function, were shown to be upregulated at 500 nT and 0.2 T, but downregulated at 16 T. 12,13 These opposite changes may contribute to the differential effects of 500 nT, 0.2 T, and 16 T on osteoblast and osteoclast.
In addition to the various reported proteins and pathways mentioned above, SMFs have also been shown to generally affect levels of cellular Ca 2þ and ROS, which are involved in multiple processes, including cell differentiation and tissue regeneration.61]69 Moreover, SMFs are also indicated to affect tissue regeneration and stem cell differentiation by changing ROS levels. 48,60,78,86,88The SMF-induced changes Ca 2þ and ROS are likely due to the effects of SMFs on cell membrane, electron spin, and radical recombination. 4 However, as summarized in a previous review, 89 the effects of SMFs on cellular ROS levels are highly variable, which are dependent on both magnetic field parameters and cell types.In fact, the exact relationship and dose-dependence of SMFs and ROS are still unsolved questions in this field.
However, it should be noted that the above-mentioned molecules and pathways changes are all from the biological point of view.In fact, the most fundamental mechanism lies in physics and biophysics.The mechanisms of SMFs on biological systems mainly include the induction of electric fields and currents, magnetic forces and torques on molecules and cells as well as influence of electron spin states. 78,80,89,90or example, SMF can induce the alignment of cytoskeleton due to the magnetic torque and diamagnetic anisotropy. 4SMF can modulate ROS level because they can change the electron spin state. 78,80,91owever, how to fine-tune the SMF parameters to precisely regulate the complicated biological systems is still a challenging question in the field.

IX. CONCLUSION AND FUTURE PERSPECTIVES
With the advances and increasing demand for regenerative medicine, SMFs have been explored for their potential applications in this aspect.Most current studies were carried out at the stem cell level, and most of which reported positive effects of SMFs on stem cell proliferation, differentiation, and cell survival, while a few studies showed the opposite effects.This variation is likely due to the different SMF parameters, treatment procedures, and cell types, which can all lead to inconsistent outcomes.However, it is interesting that for animal investigations, all studies have shown the beneficial effects of SMFs, especially in prevention/treatment of osteoporosis, fracture healing and bone regeneration, as well as wound healing and dental application (Fig. 1).This is probably due to the fact that animal studies are usually carried out on aspects and parameters that have been proven to be effective in cellular experiments.Based on the reports in the literature, we predict that the applications of 0.1-1 T moderate SMFs on human bodies are likely to produce beneficial effects on bone regeneration and wound healing.From the practical point of view, 0.1-0.5 T SMFs are relatively easy to generate, either by permanent magnets or by electromagnets, which makes them more practical to be used on human  bodies.In the meantime, we believe that the potentials of SMFs will be further revealed after more systematic investigations both in vitro and in vivo, which include identifying systems that can benefit from SMF treatment, optimizing SMF parameters, as well as unraveling the exact physical and biophysical mechanisms that mediated all the reported biological changes.Human studies are strongly encouraged, especially in the fields of osteoporosis, fracture healing, bone regeneration, and wound healing.
but Sarvestani et al. concluded that there was no significant change in the cell cycle. 71This is actually not surprising because they used different treatment time (96 h in Javani et al.'s study while only 5 h in Sarvestani et al.'s study) and different measurement readout (cell survival and proliferation in Javani et al.'s study while cell cycle in Sarvestani et al.'s study)

TABLE I .
Effects of SMFs on bone regeneration.Bone marrow mesenchymal stem cells (BMSCs); periodontal ligament stem cells (PDLSCs); Wharton's jelly mesenchymal stem cells (WJMSCs); mandibular condylar chondrocytes (MCCs); and N/A, not available.Jing et al. demonstrated the benefits of 180 mT gradient SMF on wound healing in STZ-induced diabetic rats.40Zhaoet al. found that SMF promoted wound healing after treating diabetic rats with 230 mT SMF for 21 days. 41Shang et al. found that 600 mT SMF treatment for 14 days significantly accelerated wound closure in diabetic mice.

TABLE III .
58omotional effects of SMFs on wound healing.Bone marrow mesenchymal stem cells (BMSCs); human umbilical vein endothelial cells (HUVECs); and N/A, not available.SMF stimulated human satellite cell cultures did not promote myogenic maturation of human satellite cell cultures.57Inarecent work, Yang et al. performed both in vitro and in vivo experiments to show that moderate SMFs in combination with magneticresponsive aligned fibrin hydrogel (AFG) (consists of MNPs uniformly embedded in AFG) can promote nerve regeneration.58